Diarrhea and neutropenia are common and often dose-limiting toxicities associated with clinically active chemotherapeutic agents, including irinotecan, the drug of focus in this proposal. Although irinotecan/FU/LV is considered a standard therapy in the treatment of patients with advanced colorectal cancer, a significant number of treated patients remain clinically resistant and grade Ill/IV diarrhea (approximately 30%) and neutropenia (approximately 15%) are common. These toxicities compromise the quality of life of responders and non-responders alike. Thus, there is a critical and pressing need to identify and evaluate approaches that could impact positively on the therapeutic selectivity and quality of life of patients treated with existing drugs. Studies carried out in our laboratory demonstrated that administration of double the maximum tolerated dose of irinotecan (200 mg/kg/d x 3) in rats yielded 100% lethality within 7 days of treatment with irinotecan. In contrast, when the same dose of irinotecan was combined with celecoxib, a cyclooxygenase (COX-2) inhibitor (30 mg/kg), 100% survived with no significant diarrhea. Furthermore, in rats bearing advanced ward colorectal tumor (3 gm), irinotecan yielded no significant tumor responses, while the combination with celecoxib yielded an overall response rate of 75% (50% PR and 25% CR). Studies are continuing to confirm the generalizability of this finding with other drugs and in other rodents bearing transplantable human tumors and to delineate the underlying mechanisms. These data preclinically provide a clear demonstration of improved therapeutic index of irinotecan by celecoxib and provide the basis for the design of the proposed phase I clinical trial with parallel laboratory investigations. The underlying hypotheses: 1) celecoxib protects selectively normal tissues; 2) down regulation of COX-2 by celecoxib in normal tissues results in selective restoration of the proliferation and amelioration of irinotecan toxicity; and 3) celecoxib protects against irinotecan-induced toxicity without altering the active irinotecan metabolite SN-38 to the inactive SN-38 glucuronide ratio. The specific aims are: 1) determine the maximum tolerated dose of irinotecan combined with celecoxib 400 mg PO BID. 2) assess the incidence of irinotecan-induced diarrhea in patients receiving weekly irinotecan in combination with celecoxib at 400 mg PO BID 3) Obtain pre-treatment and post-treatment evaluation of the following biological correlates in patients receiving irinotecan single agent or a combination of irinotecan and celecoxib: a) COX-2 expression; b) histopathologic evaluation with focus on mucosal damage and inflammation; and c) intestinal mucosal apoptosis; and 4) Evaluate the effect of celecoxib on the pharmacokinetic parameters of irinotecan and its metabolites. A collaborative team of scientists, medical oncologists, and pathologists is in place to assure that the proposed studies will be carried out efficiently. If we are successful in fulfilling the objectives of the proposed plan, the generalization of this approach can be tested with other drugs and other malignancies where impact on therapeutic outcome can be evaluated in phase II clinical trials. [unreadable] [unreadable]